Doctors Fear Losing Leukemia Drug Deemed Risky

The FDA's approval of Gleevec for CML in 2001 changed chemotherapy. Until then, we had attacked any cell that tried to replicate and hoped to kill the cancer faster than we killed the patient. Since then, we target the biochemical signals that drive the malignancy. Gleevec was wonderfully effective--initially--against both early and late-state CML. But while the cases that were treated early, when there was only one mutation remained in remission for years, those that had progressed further ("blast crisis") rapidly developed resistance to Gleevec.

Ponatinib was developed and launched to defeat the most common resistance mechanism to Gleevec. But the larger lesson--that cancer should be pre-empted, when the mutations are few, without waiting to tick off all the "hallmarks of cancer" has been lost on both clinicians and on the FDA. Only dermatologists reach for the scalpel (or the cyrogenics) to remove pre-cancerous lesions. And only the dermatologists are winning. For other tissues, pre-cancerous conditions aren't even called diseases, and treating them can't be remunerated under current American health insurance policies.

Brian Lee for The New York Times

That question was at the heart of a decision announced Thursday by theFood and Drug Administration to suspend sales of a leukemia drug, Iclusig, that was keeping patients alive but also significantly raising their odds of heart attacks, strokes,blindness, death and amputations.

Despite the potential consequences, several doctors who treat people with the disease, chronic myeloid leukemia, said there were patients for whom nothing else works, and whose lives depend on the drug.

“My concern is that I have patients right now who are benefiting from this medication with very few side effects, and if they’re on the end of a one-month prescription, what’s going to happen when their medication runs out?” said Dr. Brian Druker, the director of the Knight Cancer Institute at Oregon Health and Science University. “Without this medication, they won’t have long to live. My patients are panicked.”

The drug agency has said that patients who need the drug will still be able to obtain it, but that doctors will have to file applications for each patient, a process that some say is cumbersome and might leave patients tangled up in red tape, with no pills.

Dr. Michael Mauro, a leukemia specialist at Memorial Sloan-Kettering Cancer Center in New York, said that 23 leukemia specialists and three patient advocacy groups had sent the drug agency a letter saying they were concerned that the sudden withdrawal of the drug would interrupt treatment for patients with no other good options.

Iclusig, also called ponatinib, was approved in December 2012 to treat patients who had chronic myeloid leukemia that did not respond to other drugs. The disease is a relatively uncommon form of leukemia, with about 5,000 cases a year and 600 deaths in the United States. The wholesale price of the drug was $115,000 a year.

Iclusig was given accelerated approval by the drug agency under a program that allows some important drugs to reach the market quickly, without the full evidence of safety and efficacy that the agency usually requires but subject to further studies to confirm the drug’s benefit.

Critics might say Iclusig’s approval is a sign that accelerated approval can allow dangerous drugs on the market. But supporters of the program say the fact that marketing of Iclusig is being suspended is a sign that the system is working as intended.

Iclusig is part of a new generation of “targeted” drugs that act against specific biochemical defects that fuel the explosive growth of certain types of cancer. The first of these drugs for chronic myeloid leukemia was Gleevec. (Dr. Druker was one of its developers.) It revolutionized the treatment of the illness and transformed it from a death sentence into a chronic disease that people could live with for many years.

Iclusig is one of several drugs developed for patients who did not respond to Gleevec, or who became resistant to it.

But even though these powerful new drugs are specifically designed to fight cancer cells, they also find their way to other targets, including the cardiovascular system.

In a bulletin on Thursday, the drug agency said that 24 percent of patients taking Iclusig who were studied for a median of 1.3 years, and 48 percent studied for a median of 2.7 years, had suffered “serious adverse vascular events.” Those figures are unusually high, and higher than what was reported from the initial studies done before the drug was approved.

The events included blockages in blood vessels that led to heart attacks, strokes, blindness and lack of blood flow to the extremities. Some of the patients were young, in their 20s, and some had no risk factors for heart or artery disease.

A spokeswoman for the drug agency, Stephanie Yao, said that in studies of the drug to date, which involved 530 patients, at least 14 had died from cardiovascular problems.

Dr. Frank Haluska, the chief medical officer of Ariad Pharmaceuticals, the Cambridge, Mass., company that makes the drug, said the company was working with the drug agency to analyze the problems and hoped to return the drug to the market. Over all, he said, about 2,000 people have taken the drug.

In an article published Friday by The New England Journal of Medicine, Harvard researchers said that the reports of cardiovascular problems linked to ponatinib and other newer drugs (not Gleevec) lacked the kind of details that doctors need to figure out whether side effects could be prevented.

One of the authors, Dr. Javid Moslehi, a co-director of the cardio-oncology program at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, said in an interview that if, for instance, the problems were known to occur because of excessive blood clotting from a cancer drug, then patients could also be given another medication to prevent clots. Or, if the cancer drug were causing plaque to build up in the arteries, patients might be given a statin to try to prevent it.

“What we don’t want to have happen is for a good drug, ponatinib, to be killed and not given to patients,” Dr. Moslehi said.

The setbacks for the drug have also shaken its maker. Ariad’s stock has lost about 85 percent of its value since Oct. 9, when it first announced that the drug agency had halted further enrollment in clinical trials of Iclusig because of the safety concerns.

On Oct. 18, it canceled a clinical trial aimed at winning approval for the drug as an initial treatment for chronic myeloid leukemia, rather than as a treatment used only after other drugs have failed. Such an approval could have greatly expanded sales of the drug.

Some Wall Street analysts say they think that the drug can remain on the market, but might be only for those whose cancer cells have a particular mutation for which other treatments do not work.

“We expect a meaningful delay for the drug to potentially return to the market and a more modest opportunity if this were to occur,” Jonathan Eckard, an analyst at Citigroup, wrote in a note Thursday.

Analysts expect that Ariad will have to sharply cut expenses, including its work force, to preserve cash.

On Friday, Ariad’s board approved a poison pill defense apparently aimed at preventing the acquisition of additional shares by Sarissa Capital, a hedge fund that might seek to change the management. Ariad said the move was designed to preserve its ability to use accumulated losses to offset future taxes.